Vicinal difunctionalization refers to a chemical reaction involving transformations at two adjacent centers (most commonly carbons). This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition. Introduction Vicinal difunctionalization reactions, most generally, lead to new bonds at two adjacent carbon atoms. Often this takes place in a stereocontrolled fashion, particularly if both bonds are formed simultaneously, as in the Diels-Alder reaction. Activated double bonds represent a useful handle for vicinal difunctionalization because they can act as both nucleophiles and electrophiles—one carbon is necessarily electron poor, and the other electron rich. In the presence of a nucleophile and an electrophile, then, the two carbons of a double bond can act as a "relay," mediating electron flow from the nucleophile to the electrophile with the formation of two, rather than the usual one, chemical bonds. (1) Most often, the nucleophile employed in this context is an organometallic compound and the electrophile is an alkyl halide. Mechanism and stereochemistry Prevailing mechanism The mechanism proceeds in two stages: β-nucleophilic addition to the unsaturated carbonyl compound, followed by electrophilic substitution at the α-carbon of the resulting enolate. When the nucleophile is an organometallic reagent, the mechanisms of the first step can vary. Whether reactions take place by ionic or radical mechanisms is unclear in some cases. Research has shown that the second step may even proceed via single-electron transfers when the reduction potential of the electrophile is low. A general scheme involving ionic intermediates is shown below. (2) Lithium organocuprates undergo oxidative addition to enones to give, after reductive elimination of an organocopper(III) species, β-substituted lithium enolates. In any case, the second step is well described in all cases as the reaction of an enolate with an electrophile. The two steps may be carried out as distinct experimental operations if the initially formed enolate is protected after β-addition. If the two steps are not distinct, however, the counterion of the enolate is determined by the counterion of the nucleophilic starting material and can influence the reactivity of the enolate profoundly. Stereochemistry Steric approach control is common in conjugate addition reactions. Thus, in cyclic substrates, a trans relationship between substituents on the α- and β-carbons is common.